1. Field of the Invention
The present invention relates to taste masking of active pharmaceutical ingredients. In particular, it is directed to a particulate pharmaceutical formulation taste masked with a bi-layer coating and a process of producing the same.
2. Description of the Related Technology
Medication compliance is a significant challenge for patients who have difficulties swallowing, such as young children, the very elderly and patients with dysphagia. The pharmaceutical industry has developed a number of drug delivery protocols to address this challenge, including rapid in-mouth disintegrating tablets, tablets which disintegrate in liquid prior to ingestion, liquids and syrups, gums and even transdermal patches. Unfortunately, each of these methods has its own problems. For example, transdermal patches can be inconvenient or uncomfortable to use and quite expensive to produce. The flux of drug through the skin can also raise complex dosing issues.
U.S. Pat. No. 6,740,341 discloses that masking the bad taste of an active pharmaceutical ingredient (API) can make it pleasant enough to chew and swallow, therefore making it easier for patients to ingest the medication. A variety of methods have been used to mask the taste of an API. These include the use of flavorings, sweeteners, effervescent systems and various coating strategies. One particularly effective method is microencapsulating API powders by coating with ethyl cellulose, a mixture of ethyl cellulose and hydroxypropyl cellulose, or other cellulose derivatives, to provide chewable taste-masked medications. U.S. Pat. No. 6,740,341 also discloses a taste masking formulation that includes a taste masking layer and a spacing layer over the drug particles. The drug particle sizes may be up to 1500 μm, which can introduce an undesirable gritty feeling for orodispersible dosage forms. Additionally, this formulation requires two layers of at least 5 μm thick, leading to a high polymer loading, which may affect the size of the dosage form.
U.S. Pat. No. 5,552,152 discloses a chewable taste-masked tablet having controlled release characteristics comprising microcapsules of from about 100 μm to about 0.8 mm in diameter. The microcapsules have a pharmaceutical core of crystalline ibuprofen and a methacrylic acid copolymer coating with sufficient elasticity to withstand chewing. Large microcapsule sizes are preferred (0.25-1 mm in diameter), because larger microcapsules are easier to manufacture and package, and less expensive to produce than smaller microcapsules. However, microcapsules of this size may fracture during chewing and release drug from the microcapsule, especially when there is an inadequate amount of plasticizer or other component included to provide sufficient elasticity. Therefore, larger sized microcapsules require greater elasticity to minimize the likelihood of fracturing during chewing.
Yang et al. discloses several processing techniques for dry coating cohesive corn starch powder with different silica particles (Yang J, Sliva A, Banerjee A, Dave, RN, Pfeffer R. Dry particle coating for improving the flowability of cohesive powders. Powder Technology, V. 158, 2005, 21-22). The nanosized silica particles provide good flowability enhancement, as compared with mono-dispersed 500 nm silica. It further taught that surface-treated hydrophobic silica is more effective in improving the flowability of corn starch particles than untreated hydrophilic silica. However, Yang et al. is only concerned with flowability and not taste masking.
Chen et al. discloses a process to deposit a very small amount of nano-sized particles (as low as 0.01% by weight) with a high degree of precision onto the surface of cohesive powders, Geldart group C powders (Chen Y, Yang J, Dave R N, Pfeffer R. Fluidization of Coated Group C Powders. AIChE Journal, V. 54, 2008, 104-121). The process improves the flowability and fluidizability of cohesive powders. Chen et al. only discusses the fluidization behavior of ideal cohesive powders such as corn starch, which is often added to pharmaceutical formulations. Chen et al. does not discuss fluidizing active pharmaceutical ingredients, which typically have irregular shapes, high surface energy, and undergo significant tribocharging. Another publication from Chen et al. discloses a process of using fluidized bed film technology to coat group C powders that are deposited with nanosize silica particles on their surface (Chen Y, Yang J, Mujumdar A, Dave, R N. Fluidized bed film coating of cohesive Geldart group C powders. Powder Technology. v189 (2009) 466-480). The examples disclosed in this paper are limited to substantially spherical cornstarch and aluminum particles.
U.S. Pat. No. 7,276,249 discloses a composition including a fibrate, preferably fenofibrate, and at least one surface stabilizer adsorbed on the surface of the fibrate particles. The fibrate particles have an effective average particle size of less than about 2000 nm.
A significant issue for prior art processes is agglomeration of API particles in traditional fluidized bed coating processes, which typically leads to particle sizes much larger than 100 μm and results in an unpleasant gritty mouth feel that make these dosages unpalatable. The present invention provides a process to produce taste masked API powders by fluidized bed coating with minimal agglomeration of drug particles. The process of present invention also requires a lower polymer loading to allow for API's having a relatively high potency.